Biology subjects

Song, J.

Publications and source records attributed to Song, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2020

Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Mounting evidence suggests that cognitive deficits associated with various neurological disorders may arise in part from a small population of dysregulated adult-born neurons in the dentate gyrus (DG). How these dysregulated adult-born neurons contribute to brain-wide network maladaptation and subsequent cognitive deficits remains unknown. Using an established mouse model with a small number of time-stamped dysregulated adult-born immature neurons and spatial memory deficits, we performed resting state functional magnetic resonance imaging and found that approximately 500 deficient immature neurons (<0.1% of total DG granule neurons) are sufficient to induce a significant decrease in the functional connectivity between DG and insular cortex (IC), two brain regions without direct anatomical connections. Furthermore, using a combination of rabies-based retrograde tracing and in vivo fiber photometry recording, we demonstrated that dysregulated adult-born neurons induce aberrant activity and synchrony in local hippocampal CA3 and CA1 regions, as well as distal medial-dorsal thalamus and IC regions during a spatial memory process. These results suggest that a few hundred dysregulated adult-born immature neurons can impact brain-wide network dynamics across several anatomically discrete regions and collectively contribute to impaired cognitive functions.

neuroscience↗

bioRxiv2020

Identification of Lysine Isobutyrylation as A New Histone Modification Mark

Short-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity, especially p300 and HAT1. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

biochemistry↗

bioRxiv2020

Recombinant SARS-CoV-2 RBD molecule with a T helper epitope as a built in adjuvant induces strong neutralization antibody response

Without approved vaccines and specific treatment, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading around the world with above 20 million COVID-19 cases and approximately 700 thousand deaths until now. An efficacious and affordable vaccine is urgently needed. The Val308 - Gly548 of Spike protein of SARS-CoV-2 linked with Gln830 - Glu843 of Tetanus toxoid (TT peptide) (designated as S1-4) and without TT peptide (designated as S1-5), and prokaryotic expression, chromatography purification and the rational renaturation of the protein were performed. The antigenicity and immunogenicity of S1-4 protein was evaluated by Western Blotting (WB) in vitro and immune responses in mice, respectively. The protective efficiency of it was measured by virus neutralization test in Vero E6 cells with SARS-CoV-2. S1-4 protein was prepared to high homogeneity and purity by prokaryotic expression and chromatography purification. Adjuvanted with Alum, S1-4 protein stimulated a strong antibody response in immunized mice and caused a major Th2-type cellular immunity compared with S1-5 protein. Furthermore, the immunized sera could protect the Vero E6 cells from SARS-CoV-2 infection with neutralization antibody GMT 256. The candidate subunit vaccine molecule could stimulate strong humoral and Th1 and Th2-type cellular immune response in mice, giving us solid evidence that S1-4 protein could be a promising subunit vaccine candidate.

bioengineering↗

bioRxiv2020

Qualitative and quantitative bioanalytical methods validation of aristolochic acid DNA adducts and application in human formalin-fixed paraffin-embedded hepatocellular carcinoma tissues

Mutation signature of aristolochic acid (AA) found in urothelial or hepatocellular carcinoma causes public concern about the cancer risk of AA. In contrast, direct evidence based on the reliable bioanalytical method for the exposure of AA is still lacking and not universal. Here, we strictly complied with the qualitative and quantitative guidance for forensic toxicological analysis: In the sample preprocessing, DNA from formalin-fixed and paraffin-embedded (FFPE) tissues was digested to single nucleotide by a series of enzymes with 70% enzymatic digestion efficiency. After protein precipitation, the samples were submitted to an ABI6500+ mass spectrometer for LC-MS/MS analysis. Ion pairs 543.2/427.2 and 543.2/395.2 of dA-AAI were selected from 5 ion pairs due to their higher LC-MS/MS response. Both these ion pairs have excellent selectivity and specificity in rat liver DNA matrix, and a linear regression range from 5 pg/mL to 200 pg/mL with the best fit and determination coefficient (r) greater than 0.99. The intra and inter batch accuracy and precision of these two ion pairs are also acceptable with less than 15% variation. The total recovery for ion pair 543.2/427.2 and 543.2/395.2 of dA-AAI was 90.06% and 90.76%, respectively. Our method has a minor matrix effect and good stability under different temperature and time conditions. With signal to noise ratio [≥] 3, 2 ion pairs (< 50 % relative abundance variation), the lower limit of quantification (LLOQ) of our method is set to 5 pg/mL([~]3.6 AAI-DNA adducts per 108 DNA bases). By using this validated bioanalytical method of dA-AAI, 165 human HCC FFPE tissues were analyzed, the total ratio of samples with peak543.2/427.2 is 17.0% (28/165), with peak543.2/395.2 is 9.09% (15/165) which yields the total ratio of samples combined peak543.2/427.2 and peak543.2/395.2 is 7.27% (12/165). Two samples are higher than 5 pg/mL under the qualitative requirements. In conclusion, we first reported a fully validated methods to analyze the DNA adducts level of aristolochic acid, which could be qualitatively and quantitatively applied to the investigation of AA exposure in the human and other species.

pharmacology and toxicology↗

bioRxiv2020

Intercellular Arc signaling regulates vasodilation

Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in DRG neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of privileged translation in vitro and in vivo. Inflammatory cues promote local translation of Arc in the skin. Arc deficient mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles, we hypothesized that intercellular Arc signaling regulates the inflammatory response in skin. We found that the excessive thermal responses and vasodilation observed in Arc defective mice are rescued by injection of Arc-containing extracellular vesicles into the skin. Our findings suggest that activity-dependent production of Arc in afferent fibers regulates neurogenic inflammation through intercellular signaling. HIGHLIGHTSO_LIRibosome profiling identifies Arc as a target of activity-dependent translation C_LIO_LIArc is present in the DRG, spinal cord, and skin C_LIO_LIInduced Arc biosynthesis in skin requires the presence of afferent fibers C_LIO_LIArc-deficient mice have exaggerated inflammation that is rescued by Arc-containing extracellular vesicles C_LI

neuroscience↗

bioRxiv2020

Genomic insights into the host specific adaptation of the Pneumocystis genus and emergence of the human pathogen Pneumocystis jirovecii

Pneumocystis jirovecii, the fungal agent of human Pneumocystis pneumonia, is closely related to macaque Pneumocystis. Little is known about other Pneumocystis species in distantly related mammals, none of which are capable of establishing infection in humans. The molecular basis of host specificity in Pneumocystis remains unknown as experiments are limited due to an inability to culture any species in vitro. To explore Pneumocystis evolutionary adaptations, we have sequenced the genomes of species infecting macaques, rabbits, dogs and rats and compared them to available genomes of species infecting humans, mice and rats. Complete whole genome sequence data enables analysis and robust phylogeny, identification of important genetic features of the host adaptation, and estimation of speciation timing relative to the rise of their mammalian hosts. Our data reveals novel insights into the evolution of P. jirovecii, the sole member of the genus able to infect humans.

evolutionary biology↗

bioRxiv2020

TRIAGE: A web-based iterative analysis platform integrating pathway and network databases optimizes hit selection from high- throughput assays.

Comprehensive and efficient gene hit selection from high throughput assays remains a critical bottleneck in realizing the potential of genome-scale studies in biology. Widely used methods such as setting of cutoffs, prioritizing pathway enrichments, or incorporating predicted network interactions offer divergent solutions yet are associated with critical analytical trade-offs, and are often combined in an ad hoc manner. The specific limitations of these individual approaches, the lack of a systematic way by which to integrate their rankings, and the inaccessibility of complex computational approaches to many researchers, has contributed to unexpected variability and limited overlap in the reported results from comparable genome-wide studies. Using a set of three highly studied genome-wide datasets for HIV host factors that have been broadly cited for their limited number of shared candidates, we characterize the specific complementary contributions of commonly used analysis approaches and find an optimal framework by which to integrate these methods. We describe Throughput Ranking by Iterative Analysis of Genomic Enrichment (TRIAGE), an integrated, iterative approach which uses pathway and network statistical methods and publicly available databases to optimize gene prioritization. TRIAGE is accessible as a secure, rapid, user-friendly web-based application (https://triage.niaid.nih.gov). O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/204917v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@7150f8org.highwire.dtl.DTLVardef@17af411org.highwire.dtl.DTLVardef@12d8f01org.highwire.dtl.DTLVardef@78c48_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

bioinformatics↗

bioRxiv2020

Decorin, a novel negative modulator of E-cadherin in inflammatory breast cancer

ABSTRACTInflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited IBC tumor growth and metastasis in vivo. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2020

Human ANKLE1 is a nuclease specific for branched DNA

ABSTRACTAll physical connections between sister chromatids must be broken before cells can divide, and eukaryotic cells have evolved multiple ways in which to process branchpoints connecting DNA molecules separated both spatially and temporally. A single DNA link between chromatids has the potential to disrupt cell cycle progression and genome integrity, so it is highly likely that cells require a nuclease that can process remaining unresolved and hemi-resolved DNA junctions and other branched species at the very late stages of mitosis. We argue that ANKLE1 probably serves this function in human cells (LEM-3 in C. elegans). LEM-3 has previously been shown to be located at the cell mid-body, and we show here that human ANKLE1 is a nuclease that cleaves a range of branched DNA species. It thus has the substrate selectivity consistent with an enzyme required to process a variety of unresolved and hemi-resolved branchpoints in DNA. Our results imply that ANKLE1 acts as a catch-all enzyme of last resort that allows faithful chromosome segregation and cell division to occur.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2020

ATP induces protein folding, inhibits aggregation and antagonizes destabilization by effectively mediating water-protein-ion interactions, the heart of protein folding and aggregation

Many, particularly {beta}-dominant proteins, are prone to misfolding/aggregation in the crowded cells, a hallmark of ageing and neurodegenerative diseases including ALS. ATP provides energy to drive supramolecular machineries to control protein hemostasis in modern cells. Recently ATP was decoded to hydrotropically inhibit/dissolve liquid-liquid phase separation (LLPS) and aggregation/fibrillation at millimolar concentrations. We also found that by specific binding, ATP induces and subsequently dissolves LLPS, as well as inhibits fibrillation. Nevertheless, no report shows that ATP can directly induce protein folding. Here, by selecting two aggregation-prone ALS-causing proteins with the unfolded states, we successfully visualized the effects of ATP and 11 molecules with NMR directly on their folding and aggregation. The study reveals for the first time that ATP can induce folding at molar ratios of 2-8, the highest efficiency known so far. Intriguingly, this inducing-capacity comes from triphosphate, a key intermediate in prebiotic chemistry, which, however, also triggers aggregation. Most unexpectedly, upon joining with adenosine, the ability of triphosphate to trigger aggregation is shielded. Marvelously, ATP emerged to manifest three integrated abilities: to induce folding, inhibit aggregation and increase stability, that are absent in ATPP, AMP-PCP and AMP-PNP. Our study sheds the first light on previously-unknown roles of ATP in energy-independently controlling protein folding and aggregation by effectively mediating water-protein-ion interactions. Therefore, ATP might be not just irreplaceable for solving protein folding and aggregation problems simultaneously in primitive cells for Origin of Life, but also energy-independently operating in modern cells to regulate protein homeostasis fundamentally critical for physiology and pathology.

biophysics↗

bioRxiv2020

Rhesus macaques as a tractable physiological model of human ageing

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

genomics↗

bioRxiv2020

Arhopalus rusticus (Coleoptera: Cerambycidae): a new vector for pine wood nematode, Bursaphelenchus xylophilus (Nematoda: Aphelenchoididae)

In the study on the transmission of pine wood nematodes by Arhopalus rusticus, we research the ability and characteristics of Arhopalus rusticus to transmit pine wood nematodes. A total of 288 Arhopalus rusticus (female 142, male 146) were collected and 20 (female 8, male 12) of them were able to carry pine wood nematodes. Results shown that 12 beetles can transmit pine wood nematodes. Arhopalus rusticus does not eat the pine bark, but eat the pine needles. Pine wood nematodes are transmitted through the feeding bite mark on the pine needles. In addition experiments further confirmed that pine wood nematodes could transmit through pine needles.

zoology↗

bioRxiv2020

Virtual manipulation of bird tail postures demonstrates drag minimisation when gliding

Aerodynamic function of the avian tail has previously been studied using observations of bird flight, physical models in wind tunnels, theoretical modelling and flow visualization. However, none of these approaches has provided rigorously quantitative evidence concerning tail functions since: appropriate manipulation and controls cannot be achieved using live animals; and the aerodynamic interplay with wings and body challenges reductive theoretical or physical modelling approaches. Here, we have developed a comprehensive analytical drag model, calibrated by high-fidelity computational fluid dynamics (CFD), and used it to investigate the aerodynamic action of the tail by virtually manipulating its posture. The bird geometry used for CFD was reconstructed previously using stereo photogrammetry of a freely gliding barn owl and validated against wake measurements. Using this CFD-calibrated drag model, we predicted the drag production for 16 gliding flights with a range of tail postures. These observed postures are set in the context of a wider parameter sweep of theoretical postures, where the tail spread and elevation angles were manipulated virtually. The observed postures of our gliding bird corresponded to near minimal total drag.Author Summary The aerodynamic contribution of bird tails is challenging to study; strong interactions between wings, body and tail make models isolating the contributions of different body parts difficult to interpret. Further, methods for direct manipulation are limited, and confounding compensation is likely in live, free-flying birds. To circumvent these issues, we applied high-fidelity CFD to a range of measured gliding owl geometries in order to develop a comprehensive analytical drag model. This enabled the drag implications of virtually-manipulated tail postures to be explored. The theoretical postures that cause minimum drag match those used by owls. The drag model demonstrates the importance of the viscous component of drag, which is of particular relevance to fliers at the scale of birds and, increasingly, smaller UAVs.View Full Text

animal behavior and cognition↗

bioRxiv2020

From wing shape to fluid dynamics in the barn owl (Tyto alba)

Birds morph their wings and tail in order to glide under a wide range of aerodynamic conditions. Gross wing morphing has been described in a multitude of studies, but the finer details of wing morphing are still unknown. Here, we measured the changes in wing shape and pose in a barn owl, Tyto alba, when gliding across a range of fifteen self-selected speeds. We found that T. alba does not use fine-wing shape control to glide at slow speeds in steady conditions, with the measured wing shapes being highly consistent across all flights. Instead, T. alba relied upon wing postural control (gross pitch) and changes in both tail shape and pose to modulate aerodynamic force. A consistent wing shape provides an exceptional aerodynamic tool for understanding gliding flight in birds through postural change and tail morphing. This geometry was used as the basis for computational fluid dynamics simulations which gave very similar wake measurements and weight support to those measured in flight. This geometry is provided here to assist other researchers interested in exploring the fluid dynamics behind gliding flight in birds.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗

bioRxiv2020

Distinct Long-term Effects of Precision X-Radiation on Reflex Saliva Flow Rate and Tissue Integrity in a Preclinical Model of Chronic Hyposalivation

Chronic salivary hypofunction and xerostomia are common side effects of radiation therapy which is an essential component in the curative management in patients with head & neck cancers. Over the years, improvements in delivery techniques such as image-guided intensity modulated radiation therapy have led to improvement in cancer management but chronic hyposalivation continues to be a challenge that causes long-term health implications resulting in compromised quality of life. Recent advances in salivary stem cell research promise new frontier in the treatment of radiation-induced hyposalivation by initiating regeneration of radiation-damaged salivary parenchymal cells. Lack of a standard preclinical immunodeficient model to assess radiation-induced changes objectively and quantitatively in salivary flow rates will impede rapid progress towards the development of cellular therapies for chronic salivary dysfunction and attendant xerostomia. Herein, we report the first fully characterized novel cone-beam computed tomography (CBCT)-guided precision ionizing radiation (IR) induced chronic hyposalivation model in radiosensitive, immunodeficient transgenic NSG-SGM3 mice expressing three human cytokines including c-KIT ligand/stem cell factor. Additionally, we also report a novel and instantaneous method to objectively assess the kinetics of pilocarpine-stimulated salivary flowrate. Comprehensive structural and functional characterization of salivary glands revealed previously unknown and highly complex gender, age, IR dose and salivary gland subtype-specific effects of salivary-ablative precision IR.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2020

Silent dissemination of plasmid-borne tigecycline resistance gene tet(X6) in livestock-associated Acinetobacter towneri

A tigecycline-resistance gene, tet(X6), was detected on a 159-kb novel plasmid carried by a tigecycline-susceptible livestock-associated Acinetobacter towneri isolate. The genetic context of tet(X6) ({Delta}ISVsa3-tet(X6)-abh-guaA-ISVsa3) is highly similar with that of the other plasmid-borne tet(X) variants. The 23-Ala residue of the first FAD binding site conferred higher activity to Tet(X6) than the 23-Gly reside conserved in the other plasmid-borne tet(X)s. To our knowledge, this is the first report of tet(X6) carried by the plasmid.

genetics↗

bioRxiv2020

Recognition memory via repetition suppression in mouse hippocampal dorsal CA2 pyramidal neurons expressing the vasopressin 1b receptor

Recognition memory, often compromised in psychiatric disorders, is a major component of declarative memory, which permits the realization that an event, object or social subject has been previously encountered. The CA2 region of the dorsal hippocampus (dCA2) is involved in social memory and responds to novel objects, in time and space. However, it remains unclear how these neurons encode either social or inanimate object recognition. Here, we show that in dCA2, encoding of social recognition memory entails suppression of pyramidal neurons activity leading to a sparse representation of the familiar conspecific. We discuss the neural coding scheme by which dCA2 pyramidal neurons contribute to social memory.

neuroscience↗

bioRxiv2020

Establishment of a stable transgenic g6pdM1315-1443 zebrafish line with glucose-6-phosphate dehydrogenase deficiency

ABSTRACTGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzymopathy in humans and is associated with a predisposition to hemolysis. However, there are few animal models to that adequately mimic associated human disease states that could be used to evaluate strategies to address clinical syndromes attributable to G6PD deficiency. In the present study, we aimed to establish a stable transgenic zebrafish model of G6PD deficiency that recapitulates the clinical manifestations of G6PD deficiency. We incorporated a stable transgene of G6PD lacking nucleotides from 1315 to 1443 denoted Tg(zgata1:g6pdM1315-1443-egfp). Functional analysis showed that Tg(zgata1:g6pdM1315-1443-egfp) transgenic zebrafish demonstrate a decrease in g6pd activity, reduced GSH levels and hemoglobin content, and increases in pericardial edema in response to α-naphthol exposure, similar to human subjects with G6PD deficiency. We detected no other significant phenotypic abnormalities compared to controls. Taken together, these observations indicate that the Tg(zgata1:g6pdM1315-1443-egfp) zebrafish line mirrors key clinical manifestations of G6PD deficiency in humans. This model may facilitate mechanistic studies and promote translational research related to G6PD deficiency.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗